Gut Microbiota and Ferroptosis in Colorectal Cancer: A Comprehensive Review of Mechanisms and Therapeutic Strategies to Overcome Immune Checkpoint Resistance.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients-those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors-derive little benefit from current immunotherapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal accumulation of lipid peroxides, has emerged as a promising antitumor mechanism that can interact with and modulate antitumor immunity. Concurrently, the gut microbiota exerts powerful control over host metabolism and immune tone through microbial community structure and metabolite production; accumulating evidence indicates that microbiota-derived factors can either sensitize tumors to ferroptosis (for example, via short-chain fatty acids) or confer resistance (for example, indole-3-acrylic acid produced by Peptostreptococcus anaerobius acting through the AHR→ALDH1A3→FSP1/CoQ axis). In this review we synthesize mechanistic data linking microbial ecology, iron and lipid metabolism, and immune regulation to ferroptotic vulnerability in CRC. We discuss translational strategies to exploit this "microbiota-ferroptosis" axis-including precision microbiome modulation, dietary interventions, pharmacologic ferroptosis inducers, and tumor-targeted delivery systems-and we outline biomarker frameworks and trial designs to evaluate combinations with ICIs. We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges.